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Repression of the interferon signal transduction pathway by the adenovirus E1A oncogene
Abstract:
The signal transduction pathway initiated by type I interferon (alpha and beta interferons) is inhibited by expression of the adenovirus type 5 E1A oncogene. Cotransfection analyses with the E1A oncogene and an interferon-stimulated reporter gene show that mutations within an amino-terminal domain of the E1A oncoprotein are defective in transcriptional repression. Cotransfection experiments also revealed that the transcriptional repression is mediated through the interferon-stimulated response element (ISRE) found within the promoter of interferon-stimulated genes. Since interferon treatment activates a latent cytoplasmic DNA-binding factor that can recognize the ISRE and subsequently stimulate transcription, the appearance of this factor was analyzed in a cell line that constitutively expresses the E1A oncogene. The DNA binding activity of this transcriptional activator was found to be inhibited in the E1A-expressing cell line. In vitro cytoplasmic mixing experiments with extracts from control and E1A-expressing cells identified a specific component of this multimeric transcription factor to be defective.
Insights
Adenovirus E1A oncogene inhibits type I interferon signaling by blocking a key transcription factor. This defect, localized to the E1A N-terminal domain, impairs interferon-stimulated gene expression.
Area of Science:
- Molecular Biology
- Virology
- Cellular Biology
Background:
- Type I interferons (IFN-α/β) are crucial for antiviral immunity.
- Adenovirus E1A oncogene is known to interfere with cellular processes.
- Interferon signaling involves transcriptional activation of specific genes.
Purpose of the Study:
- To investigate the mechanism by which adenovirus type 5 E1A oncogene inhibits type I interferon signaling.
- To identify the specific viral protein domain and cellular factors involved in this inhibition.
Main Methods:
- Cotransfection assays using E1A oncogene and interferon-stimulated reporter genes.
- Analysis of mutations within the E1A oncoprotein's amino-terminal domain.
- Assessing DNA-binding activity of interferon-stimulated transcription factors in E1A-expressing cells.
- In vitro cytoplasmic mixing experiments.
Main Results:
- Adenovirus type 5 E1A oncogene expression inhibits the type I interferon signal transduction pathway.
- Mutations in the E1A N-terminal domain impair transcriptional repression of interferon-stimulated genes.
- E1A inhibits the DNA-binding activity of a cytoplasmic transcription factor that recognizes the interferon-stimulated response element (ISRE).
- A specific component of this multimeric transcription factor is defective in E1A-expressing cells.
Conclusions:
- The adenovirus E1A oncogene disrupts type I interferon responses by inhibiting a critical transcription factor.
- The N-terminal domain of E1A is essential for this inhibitory function.
- This viral interference mechanism targets the ISRE-binding transcription factor, impacting cellular antiviral defenses.